AN IMPROVED PROCESS FOR THE PREPARATION OF HIGHLY PURE

PALIPERIDONE

This application claims priority from Indian Patent Application no 2543/MUM/2010 filed on 14 ^th September 2010 and Indian Patent Application no 2120/MUM/2011 filed on 26 ^th July 2011 which is a Patent of Addition of prior filed Indian Patent Application Number 2543/MUM/2010 filed on 14 ^th September 2010, titled "An improved process for the preparation of highly pure Paliperidone".

TECHNICAL FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of highly pure paliperidone of formula-I;

Formula-I

Particularly, the present invention relates to the production friendly process for the preparation of highly pure paliperidone substantially free from impurity namely, keto-paliperidone.

More particularly, the present invention relates to the process for the preparation of highly pure paliperidone having particle size below 60 microns which can be directly obtained by crystallization without any further processing steps. BACKGROUND OF THE INVENTION:

Paliperidone (sold as INVEGA, INVEGA Sustenna), also known as 9-hydroxyrisperidone, is an atypical antipsychotic. Chemically, paliperidone is the primary active metabolite of the older atypical antipsychotic risperidone (paliperidone is 9-hydroxyrisperidone, i.e. risperidone with an extra hydroxyl group). It is indicated for the acute and maintenance treatment of schizophrenia.

Paliperidone, chemically known as (3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l- piperidinyl]ethyl]6,7,8,9-tetra-hydro-9-hydroxy-2-methyl-4H- pyrido[l,2-a]pyrimidin-4-one) and has the following structural formula-I.

Formula-I

US 4,804,663 and US 5,158,952 describe processes for the preparation of 3-piperidinyl-l,2- benzisoxazole derivatives along with their pharmaceutical compositions and methods of use. The processes for synthesizing paliperidone and related compounds are disclosed in US 5,158,952; US 5,254,556 and US 5,688,799.

US 5,158,952 (hereinafter referred to as the '952 patent) discloses the synthetic process for the preparation of Paliperidone; a synthetic scheme has been depicted as Scheme 1. et

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydr o-4H-py ri do[1 , 2-a] py ri m i di n-4-one

Formula-I

Formula-IV

Scheme-I

9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one of formula (III) is a key intermediate useful for preparation of paliperidone. '952 and US 5,254,556 (hereinafter referred to as the '556 patent) discloses the process for preparing the key intermediate of formula (III). 3-(benzyloxy)pyridine-2-amine of formula (II) is reacted with 3 -acetyl dihydrofuran-2- (3H)-one of formula (V) in presence of activating agent, followed by treatment with ammonium hydroxide at 90°C for 5 hours to yield the compound of formula-Ill. The activating reagent includes halogenating reagent such as, phosphoryl chloride, phosphoryl bromide, phosphorous trichloride, and thionyl chloride. The reaction mass is extracted with trichloromethane and then subjected to chromatographic purifications using chloroform and methanol and further recrystallized from isopropanol. The chromatographic purification process is not commercially viable. The process results in formation of significant impurities due to the reaction of compound of formula (II) with the compound of formula (V). The compound of formula (III) is further reduced to 3-(2-chloroethyl)-9-hydroxy-2-methyl- 6,7,8,9-tetrahydro-4H-pyrido[l,2-a]-pyrimidin-4-one of formula (IV) by using palladium on carbon as a catalyst and in presence of methanol, which is further condensed with 6-fluoro-3- piperidin-4-yl-l ,2-benzisoxazole hydrochloride of formula (VI) in presence of phase transfer catalyst to yield paliperidone of formula-I.

Paliperidone obtained by the process of '952 patent does not have satisfactory purity for pharmaceutical use. Unacceptable amount of impurities are generally formed along with the paliperidone. In addition, the process involves the additional step of column chromatographic purifications. Methods involving column chromatographic purification are generally undesirable for large-scale operations thereby making the process commercially unfeasible and inefficient.

Like any synthetic compound, paliperidone contain extraneous compounds or impurities that can come from many sources. They may be un-reacted starting materials, by-products of reaction, products of side reaction, and/or degradation products. To meet the regulatory quality norms, identification, isolation, synthesis and characterization of the impurities followed by their control to the ICH levels in the final drug compound is a must.

Potential impurities of paliperidone has been disclosed in US 2008/0281 100 Al, US 2008/0171876 Al and US 2009/0247553 Al which are 3-[2-[4-(6-fluorobenzo[d]isoixazol-3-yl)- l-oxypiperidin-l-yl]ethyl-7-4-methyl-l ,5 diazabicyclom.;[4.4.0]deca-3-5-dien-2-one (PLP-NO) having the following structural formula;

2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-piperidin-l-carboxylix acid]-7-hydroxy-2-methyl-6,7,8,9- tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one-3-yl-ethyl ester (PLP-Car) having the following structural formula;

and

3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl ]-2-methyl-7,8-dihydro-6H- pyrido[l,2-a]pyrimidin-4,9-dione (keto paliperidone) having the following structural formula;

Keto-Paliperidone

A number of purification processes for the purification of paliperidone are available in the art but each one has its own drawback. Many of purification processes known in the art makes use of reducing agents in order to control the keto-paliperidone or multiple number of purification process with a huge volume of solvent (60 to 80 volumes of solvent per gram of crude paliperidone), which make process in-efficient as huge amount of solvent is required and very big reactors are required to fullfil the process requirements, and this in turn restricts the batch size in the production. Another drawback is related to overall yield of paliperidone obtained which is very less resulting in extremely high cost and low throughput.

The paliperidone is dissolved in suitable alcoholic solvent (50 to 70 times), the solution is treated with the reducing agent and the solution obtained is partially concentrated to get the pure paliperidone as a crystalline solid which is filtered and dried to yield 50 to 55 % of product having lesser amount of keto-paliperidone.

Hence, there is a need of a simple, efficient and production friendly process for the preparation of paliperidone having high purity, high yield and high throughput.

OBJECTS OF THE INVENTION:

An object of the invention is to provide an improved process for the preparation of paliperidone which is a simple, efficient, production friendly, commercially viable and economical process.

Another object of the invention is to provide an improved process for the preparation of highly pure paliperidone which is substantially free from impurity namely, keto-paliperidone.

Another object of the invention is to provide an improved process for the preparation of highly pure paliperidone with good yield and quality.

Another object of the invention is to provide an improved process for the preparation of highly pure paliperidone without use of any reducing agent for controlling impurity namely, keto- paliperidone.

Another object of the invention is to provide an improved process for the preparation of highly pure paliperidone where the process is simple, efficient, production friendly, commercially viable and economical as it does not involve huge quantity of solvent volumes thus reducing the effluents and increasing the through-put. Yet another object of the present invention is to provide an improved process for the preparation of pharmaceutically acceptable paliperidone of formula-I where paliperidone is obtained having particle size below 60 microns by simple crystallization techniques.

DETAILED DESCRIPTION:

An improved process for the preparation of paliperidone of formula-I of the invention is illustrated in scheme-II;

According to the invention there is provided an improved process for the preparation of paliperidone of formula-I; the said process comprising;

a. Condensing 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-p yrido[l ,2-a]- pyrimidin-4-one of formula (IV) with 6-fluoro-3-piperidin-4-yl-l,2-benzisoxazole hydrochloride of formula (VI) or a salt thereof in presence of solvent, base, and a catalyst and isolating the crude paliperidone;

b. Purifying the crude paliperidone by treating it with solvent in presence of base at reflux temperature to obtain clear solution, cooling the solution to crystallize out paliperidone, filtering and drying the crystallized pure paliperidone.

The step (b) of the invention further comprising suspending the wet material obtained from the step (b) in a base and heating the mixture optionally under reduced pressure; filtering and drying the wet product under vacuum to obtain pure paliperidone.

The solvent used in step (a) is selected from group comprising of toluene, ethyl acetate, acetonitrile, tetrahydrofuran, methylene chloride, ethylene chloride, diglyme, cyclohexane, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide or Cj to C ₆ straight or branched chain alcohols such as methanol, ethanol, isopropanol, n-propanol, or mixture thereof. Preferably, the solvent used in step (a) is selected from methanol, acetonitrile, acetone, isoprbpyl alcohol, tetrahydrofuran or 2-methyl tetrahydrofuran. More preferably, the solvent used in step (a) is selected from acetonitrile or methanol.

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7 6-fluoro-3-piperidin-4-yl-1 ,2-

,8,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidi benzisoxazole.HCl

n-4-one

Form

SCHEME II

The base used in step (a) is either organic base or inorganic base. The inorganic base is selected from group comprising of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, and like. The organic base is selected from diisopropyl ethyl amine, di-isopropyl amine, pyridine, triethyl amine and the like. Preferably, the base used in step (a) is potassium carbonate or di-isopropyl amine.

The catalyst used in step (a) is selected from organic or inorganic catalyst. The organic catalyst is selected from l,8-Diazabicycloundec-7-ene (DBU) or 1,5- Diazabicyclo(4.3.0)non-5-ene (DBN) or dimethylaminopyridine and like. Preferably, the organic catalyst used in step (a) is l,8-Diazabicycloundec-7-ene (DBU).

The inorganic catalyst is selected from groups comprising alkali, metal iodide such as but not limited to sodium iodide, potassium iodide, lithium iodide and the like. Preferably, the alkali metal iodide used in step (a) is potassium iodide.

The condensation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-p yrido[l,2- a]-pyrimidin-4-one of formula (IV) with 6-fluoro-3-piperidin-4-yl-l,2-benzisoxazole hydrochloride of formula (VI) or a salt thereof of step (a) is carried out at a temperature ranging from 40°C to 100°C; preferably at the temperature ranging from 45°C to 80°C.

The time required for completion of the reaction of step (a) is from 5 to 60 hours; preferably, from 20 to 50 hours; more preferably, from 30 to 40 hours.

According to one of the embodiment of the invention, the crude paliperidone is isolated from the reaction mass of step (a) by cooling the reaction mass to precipitate out the solid, filtering the solid containing inorganic salts, treating the solid with water and filtering and drying the crude paliperidone which is free of inorganic salts. The crude paliperidone is optionally dried under vacuum at 50°C to 60°C till constant weight is achieved.

According to another of the embodiment of the invention, the crude paliperidone is isolated from the reaction mass of step (a) by cooling the reaction mass to precipitate out the solid, filtering the solid containing inorganic salts, treating the solid with water and water immiscible organic solvent, separating the organic phase containing paliperidone from the aqueous phase, optionally washing the organic phase with alkaline water and distilling out the solvent from the organic phase to obtain the crude paliperidone which is directly used for purification step (b). According to yet another embodiment of the invention, the crude paliperidone is isolated from the reaction mass of step (a) by distilling out the solvent followed by adding the water and water immiscible organic solvent to the residue, separating the organic phase containing paliperidone from the aqueous phase, optionally washing the organic phase with alkaline water and distilling out the solvent from the organic phase to obtain the crude Paliperidone which is directly used for purification step (b).

The alkaline water used for washing the organic phase containing paliperidone is selected from solution of alkali metal hydroxides, solution of alkali metal carbonates, alkali metal bicarbonate or ammonia or the like.

The water-immiscible solvent used for the isolation of paliperidone is selected from group comprising chlorinated hydrocarbons such as methylene chloride, ethylene chloride, trichloromethane and carbon tetrachloride and the like. Preferably; the water-immiscible solvent used for the isolation of paliperidone is methylene chloride.

The solvent used in step (b) is selected from group comprising C ₃ to C ₆ ketone, N- methylpyrrolidone, C ₃ to C ₆ amides, propylene glycol, dimethylsulfoxide, Cj to C ₆ straight or branched chain alcohols such as methanol, ethanol, isopropanol, n-propanol or mixture thereof, acetonitrile, alkyl acetates, C ₂ to C ₈ ethers including tetrahydrofuran, 2-methyl tertahydrofuran and the likes. Preferably, the solvent used in step (b) is selected from acetone, isopropyl alcohol, tetrahydrofuran or 2-methyl tetrahydrofuran. More preferably, the solvent used in step (b) is tetrahydrofuran.

In the purification step (b), the crude paliperidone is treated with solvent in presence of base at temperature ranging from 40°C to 80°C to obtain clear solution which is cooled to crystallize out pure paliperidone. Preferably, the crude paliperidone is treated with solvent in presence of base at temperature ranging from 50°C to 70°C. The clear solution obtained in step (b) is then gradually cooled to temperature ranging from 0° to 30°C; preferably 0° to 10°C; most preferably 0° to 5°C for crystallizing out the pure paliperidone.

The base used in the purification step (b) is selected from inorganic base such as liquor ammonia, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like or organic base such as diethyl amine, triethyl amine, diisopropyl amine, and the like. Preferably, the base used in the purification step (b) is liquor ammonia. The concentration of ammonia is ranging from 1 to 30 weight percent; preferably 4 to 15 weight%, more preferably 4 to 7 weight%.

The purification step (b) is carried out at pH ranging from 6 to 14; preferably from 8 to 10.

The step (b) of the invention further optionally comprising suspending the wet material obtained from the step (b) in 4 to 7 % of liquor ammonia and heating the mixture at temperature ranging from 30°C to 80°C; preferably 50°C to 70°C optionally under reduced pressure; filtering and drying the wet product under vacuum to obtain pure paliperidone.

The pure paliperidone is dried at temperature ranging from 40 to 100°C, preferably at temperature ranging from 50°C to 80°C under vacuum.

According to the invention, yield of pure paliperidone is in the range of 80 to 85 % and is substantially free from keto-paliperidone impurity.

According to process of the invention, the pure paliperidone obtained has particle size d (0.50) below 60 micron and can be directly used for formulation, therefore does not require separate process to reduce particle size which is acceptable / required for formulation. According to invention the pure dried crystallized paliperidone is further optionally purified by suspending or dissolving the pure dried crystallized paliperidone in a mixture of solvent and base at a temperature ranging from 30°C to 80°C followed by cooling the suspension and filtering and drying the wet product at temperature ranging from 40°C to 100°C under vacuum to obtain pure paliperidone.

The solvent used for further purifying the dried crystallized paliperidone is selected from group comprising C ₃ to C ₆ ketone, N-methylpyrrolidone, C ₃ to C ₆ amides, propylene glycol, dimethylsulfoxide, Q to C ₆ straight or branched chain alcohols such as methanol, ethanol, isopropanol, n-propanol or mixture thereof, acetonitrile, alkyl acetates, C ₂ to C ethers including tetrahydrofuran, 2-methyl tetrahydrofuran and the like. Preferably, the solvent is selected from acetone, isopropyl alcohol, tetrahydrofuran or 2-methyl tetrahydrofuran. Most preferably, the solvent is acetone.

The base used for further purifying the pure dried crystallized paliperidone is selected from inorganic base like liquor ammonia, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like or organic base like, diethyl amine, triethyl amine, diisopropyl amine and the like. Preferably, the basse is liquor ammonia.

Further purification of the pure dried crystallized paliperidone yields paliperidone in the range of 70% to 75%.

The purity of Paliperidone obtained according to the invention is at least 99.85%.

According to the invention, the pure paliperidone obtained by further purification of pure dried crystallized paliperidone has particle size d (0.50) below 40 micron and can be directly used for formulation, therefore do not require separate process to reduce particle size which is acceptable / required for formulation. It was found that the use of liquor ammonia in combination with suitable solvent during the crystallization of paliperidone drastically reduces impurity, namely the keto paliperidone in a single crystallization step with higher yield of around 80% to 85%, which otherwise requires multiple crystallization and huge amount of solvent quantity (50 to 70 parts per part of paliperidone). Thus the present invention eliminates multiple crystallization thereby reduces consumption of solvent and hence reduces generation of effluents. Multiple crystallization reduce yield to 50 to 55%. However, the present invention eliminates multiple crystallization, use of huge amount of solvent and improves yield.

The second advantage of using base in combination with suitable solvent is to increase the dissolution of paliperidone for crystallization process, thereby requiring minimum dissolution volume (9.5 - 1 1 parts per part of crude paliperidone) for crystallization process, which increases the efficiency of process, thereby reducing the cost and increasing throughput of the process.

The third advantage of the developed process is to obtain the desired particle size during the purification and hence eliminating separate process to reduce particle size which is required for formulation. Paliperidone obtained according to the invention has particle size below 60 microns, preferably below 40 microns by simple crystallization techniques.

Thus, improved process for the preparation of paliperidone of the invention is a simple, efficient, production friendly, commercially viable and economical process. Paliperidone obtained according to the invention is highly pure and substantially free from keto-paliperidone impurity without affecting yield. The present process eliminates the use of reducing agent for controlling keto paliperidone impurity.

The present invention is illustrated by the following examples, which is not intended to limit the effective scope of the invention. Example 1

8.0L of acetonitrile, 1.0 Kg (4.12 moles) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H- pyrido[l,2-a]pyrimidin-4-one, 100.0 gm (0.602 moles) of potassium iodide, 1.42 kg (10.27 moles) of potassium carbonate and 1.11 kg (4.32 moles) of 6-fluoro-3(4-piperidinyl)-l ,2- benzisoxazole hydrochloride were charged. The reaction mass was heated to 65-70°C. The completion of reaction was monitored by HPLC. The reaction mass was cooled to 25-30°C and stirred for 30 min. and centrifuged. The cake obtained was washed with 1.0 L of acetonitrile. Weight of wet product containging paliperidone and inorganic salts was 3.70 kg, HPLC purity of paliperidone: 97.50%, keto-paliperidone impurity: 0.44%. The wet product obtained was further used for purification process.

Example 2

8.0L of methanol, 1.04 Kg (4.28 moles) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H- pyrido[l,2-a]pyrimidin-4-one, 1.10 kg (10.89 moles) of triethyl amine and 1.0 kg (3.89 moles) of 6-fluoro-3(4-piperidinyl)-l,2-benzisoxazole hydrochloride were charged. The reaction mass was heated to reflux. The completion of reaction was monitored by HPLC. The reaction mass was cooled to 25-30°C and further chilled to 0-5°C, stirred for 30 min. and centrifuged. The cake obtained was washed with 0.5 L of chilled methanol. Weight of wet product containing paliperidone and inorganic salts was 1.0 kg, HPLC purity of paliperidone: 98.88%, keto- paliperidone impurity: 0.05%. The wet product obtained was further used for purification process.

Example 3

5.0L of methanol, 1.04 Kg (4.28 moles) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H- pyrido[l,2-a]pyrimidin-4-one, 0.92 kg (9.09 moles) of di-isopropylamine and 1.0 kg (4.32 moles) of 6-fluoro-3(4-piperidinyl)-l,2-benzisoxazole hydrochloride were charged. The reaction mass was heated to reflux. The completion of reaction was monitored by HPLC. The reaction mass was cooled to 25-30°C and further chilled to 15-20°C, stirred for 60 min. and centrifuged. The cake obtained was washed with 0.5 L of chilled methanol. Weight of wet product containing paliperidone was 1.9 kg, HPLC purity of paliperidone: 96.18%, keto-paliperidone impurity: 0.05%. The wet product obtained was dried at 50-55°C and further used for purification process.

Dry weight of crude paliperidone: 1.1 kg Example 4

5.0L of methanol, 1.04 Kg (4.28 moles) ^' of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H- pyrido[l,2-a]pyrimidin-4-one, 0.92 kg (9.09 moles) of di-isopropylamine, 0.1 kg of 1,8- Diazabicycloundec-7-ene (DBU) and 1.0 kg (4.32 moles) of 6-fluoro-3(4-piperidinyl)-l ,2- benzisoxazole hydrochloride were charged. The reaction mass was 55-60°C. The completion of reaction was monitored by HPLC. The reaction mass was cooled to 25-30°C and further chilled to 15-20°C, stirred for 60 min. and centrifuged. The cake obtained was washed with 0.5 L of chilled methanol. Weight of wet product containing paliperidone was 1.9 kg, HPLC purity of paliperidone: 97.15%, keto-paliperidone impurity: 0.30%. The wet product obtained was obtained was dried at 50-55°C and further used for purification process.

Dry weight of crude paliperidone: 1.5 kg

Example 5

The wet product obtained in Example- 1 was suspended in purified water (15.0 L) and the mixture was heated to 70-80°C and maintained for 60 min. The reaction mass was then hot filtered and the cake was washed with purified water (1.0 L). The wet material was dried under vacuum at 50-60°C till constant weight was achieved. Yield of paliperidone: 1.50 kg; HPLC purity of paliperidone: 98.5%; keto paliperidone impurity: 0.65 % by HPLC. Example 6

The wet product obtained in Example-2 was suspended in purified water (10.0 L) and the mixture was heated to 70-80°C and maintained for 60 min. The reaction mass was then hot filtered and the cake was washed with purified water (1.0 L). The wet material was dried under vacuum at 50-60°C till constant weight was achieved. Yield of paliperidone: 0.90 kg; HPLC purity of paliperidone: 98.78%; keto paliperidone impurity: 0.06 % by HPLC.

Example 7

Crude paliperidone (0.15 Kg) obtained in example-5, tetrahydrofuran (1.15 L) and liquor ammonia (495 ml) were charged to round bottom flask. The reaction mass was heated to reflux temperature to obtain clear solution and was maintained at refluxed temperature for 60 min. The mixture was then gradually cooled to 0°C in a period of 90 to 120 min. The precipitated compound was stirred for 60 min at 0°C to 5°C and then filtered and washed with 0.15 L purified water. Weight of wet product was 0.28 kg.

Wet product obtained was treated with liquor ammonia (1.80 L) and the mixture was heated to 60°C -65°C for 2 hours. The reaction mass was then hot filtered, wet cake obtained was washed with purified water (0.24 L) and dried under vacuum at 70°-75°C till constant weight was achieved. Yield of pure paliperidone: 0.13 kg; HPLC purity of paliperidone: 99.86%, keto paliperidone impurity: 0.09 %.

The ruggedness of the experiment (Example-7) has been established by performing the experiments with crude paliperidone containing the varied percentage of keto-paliperidone in it. The content of keto-paliperidone impurity was monitored before and after purification and the results obtained are given in Table 1. Table-I: Experimental evidence for the Elimination of keto-paliperidone using THF-Liquid ammonia along with the PSD data of the obtained paliperidone.

Example 8

Wet paliperidone (3.7 kg) obtained in example- 1, purified water (10 L), and dichloromethane (31.5 L) were charged to the flask. The suspension formed were stirred for 30 min and layers were allowed to settle for 30 min. Dichloromethane layer was separated from the aqueous phase. The dichloromethane layer was washed with purified water (7.5 L), and treated with activated carbon (150 gm). The organic layer was filtered over hyflo bed. The bed was washed with dichloromethane (800 ml) and combined the washing with the filtrate. The filtrate was subjected to distillation under vacuum to obtain the crude paliperidone.

The crude paliperidone obtained was treated with tetrahydrofuran (1 1.55 L), and liquor ammonia (4.95 L), heated to reflux temperature to obtain clear solution and maintained for 60 min. The reaction mass was gradually cooled to 0° C to 5°C and stirred for 60 min. The precipitate obtained was filtered and washed with purified water (1.5 L). Weight of wet product = 2.8 kg. Wet product (2.8 kg) obtained was treated with liquor ammonia (18 L) and the mixture was heated to 60°C -65°C for 2 hours. The reaction mass was then hot filtered, wet cake obtained was washed with purified water (2.4 L) and dried under vacuum at 70°-75°C till constant weight was achieved. Yield of pure paliperidone: 1.3 kg; HPLC purity of paliperidone: 99.89%, keto paliperidone impurity: 0.07 %; PSD; d (0.5) = 43 microns

Example 9

Wet paliperidone (1.0 kg) obtained in example-2, purified water (10 L), and dichloromethane (21.0 L) were charged to the flask. The suspension formed was stirred for 30 min and layers were allowed to settle for 30 min. Dichloromethane layer was separated from the aqueous phase. The dichloromethane layer was washed with purified water (7.5 L), and treated with activated carbon (150 gm). The organic layer was filtered over hyflo bed. The bed was washed with dichloromethane (400 ml) and combined the washing with the filtrate. The filtrate was subjected to distillation under vacuum to obtain the crude paliperidone.

The crude paliperidone obtained was treated with tetrahydrofuran (6.93 L), and liquor ammonia (2.97 L), heated to reflux temperature to obtain clear solution and maintained for 60 min. The reaction mass was gradually cooled to 0° C to 5°C and stirred for 60 min. The precipitate obtained was filtered and washed with purified water (0.90 L). Weight of wet product = 1.6 kg.

Wet product (1.6 kg) obtained was treated with liquor ammonia (10.8 L) and the mixture was heated to 60°C -65°C for 2 hours. The reaction mass was then hot filtered, wet cake obtained was washed with purified water (2.4 L) and dried under vacuum at 70°-75°C till constant weight was achieved. Yield of pure paliperidone: 0.80 kg; HPLC purity of paliperidone: 99.86%, keto paliperidone impurity: 0.04 %; PSD; d (0.5) = 45 microns Example 10:

Dry paliperidone (1.1 kg) obtained in example 3 or 4; sodium hydroxide solution (5%) (5.5 L X 3 lots), and dichloromethane (22.0 L) were charged to the flask. The suspension formed was stirred for 30 min and layers were allowed to settle for 30 min. Dichloromethane layer was separated from the aqueous phase. The dichloromethane layer was washed with purified water (5.5 L X2 lots), and treated with activated carbon (100 gm). The organic layer was filtered over hyflo bed. The bed was washed with dichloromethane (1.1 L) and combined the washing with the filtrate. The filtrate was subjected to distillation under vacuum to obtain the crude paliperidone.

The crude paliperidone obtained was treated with tetrahydrofuran 8.47L), and liquor ammonia (3.63L), heated to reflux temperature to obtain clear solution and maintained for 60 min. The reaction mass was gradually cooled to 0° C to 5°C and stirred for 60 min. The precipitate obtained was filtered and washed with purified water (1.1 L). Weight of wet product = 1.8 kg.

Wet product (1.8 kg) obtained was treated with liquor ammonia (18 L) and the mixture was heated to 60°C -65°C for 2 hours. The reaction mass was then hot filtered, wet cake obtained was washed with purified water (1.1 L) and dried under vacuum at 70°-75°C till constant weight was achieved. Yield of pure paliperidone:, 0.9 kg; HPLC purity of paliperidone: 99.88%, keto paliperidone impurity: 0.05 %; PSD.

Example 11

The pure paliperidone (1.3 kg) obtained in example-8 was treated with acetone (23.0 L), and liquor ammonia (9.86 L), and heated to reflux temperature for 2 hours. The reaction mass was gradually cooled to 0° C to 5°C and stirred for 60 min. The precipitate obtained was filtered and washed with purified water (1.5 L). Weight of wet product = 2.8 kg and dried under vacuum at 70°-75°C till constant weight was achieved. Yield of pure paliperidone: 1.23 kg; HPLC purity of paliperidone: 99.90%, keto-paliperidone impurity: 0.03%; PSD d (0.5) = 18 microns

Above experiment was repeated with paliperidone having d (0.5) of around 40 to 60 microns to obtain the paliperidone having d (0.5) of around 20 microns; the reapeated examples and their results are given in Table 2.

Table-2: PSD data of paliperidone before and after acetone-ammonia treatment.

Example 12:

The pure paliperidone (0.7 kg) obtained in example- 10 was treated with acetone (13.1 L), and liquor ammonia (4.38 L), and heated to reflux temperature for 2 hours. The reaction mass was gradually cooled to 0° C to 5°C and stirred for 60 min. The precipitate obtained was filtered and washed with purified water (0.7 L). Weight of wet product = 0.83 kg and dried under vacuum at 70°-75°C till constant weight was achieved. Yield of pure paliperidone: 0.61 kg; HPLC purity of paliperidone: 99.90%), keto-paliperidone impurity: 0.03%. Example 13:

The pure paliperidone (0.7 kg) obtained in example- 10 was treated with acetone (26.25 L), and liquor ammonia (8.75 L), and heated to reflux temperature for 2 hours. The reaction mass was gradually cooled to 0° C to 5°C and stirred for 60 min. The precipitate obtained was filtered and washed with purified water (0.7 L). Weight of wet product = 1.12 kg and dried under vacuum at 70°-75°C till constant weight was achieved. Yield of pure paliperidone: 0.58 kg; HPLC purity of paliperidone: 99.92%, keto-paliperidone impurity: 0.02%.

Example 14

The pure paliperidone (0.80 kg) obtained in example-9 was treated with acetone (15.0 L), and liquor ammonia (5.0 L), and heated to reflux temperature for 2 hours. The reaction mass was gradually cooled to 0° C to 5°C and stirred for 60 min. The precipitate obtained was filtered and washed with purified water (1.5 L). Weight of wet product = 1.70 kg and dried under vacuum at 70°-75°C till constant weight was achieved. Yield of pure paliperidone: 0.75 kg; HPLC purity of paliperidone: 99.92%, keto-paliperidone impurity: 0.03%; PSD d (0.5) = 16 microns